In recent years, high-molecular materials excellent in processability, elasticity and flexibility have been widely used as medical materials. It is expected that such materials will find wider use in artificial organs such as artificial kidneys, artificial lungs, extracorporeal circulation devices and artificial blood vessels, as well as disposable products such as syringes, blood bags and cardiac catheters. Materials of these products for medical use are required to have, in addition to sufficient mechanical strength and durability, biological safety which particularly means a property of not causing coagulation of blood upon contact therewith, i.e., antithrombogenicity.
Conventional methods for imparting antithrombogenicity to medical materials are generally classified into the following three groups:
(1) immobilizing an antithrombogenic mucopolysaccaride (e.g., heparin) or a fibrinolytic activator (e.g., urokinase) on the surface of the material; PA1 (2) modifying the surface of the material so that it carries negative charge or hydrophilicity; and PA1 (3) inactivating the surface of the material. The method PA1 (1) using heparin (hereinafter referred to as "surface-heparinizing method") is further subdivided into (A) blending of a polymer with heparin, (B) coating of the material surface with an organic solvent-soluble heparin, (C) ionic bonding of heparin to a cationic group in the material, and (D) covalent bonding of the material and heparin. PA1 (i) 0.1 to 50 mol % of a diol containing phosphorylcholine structure represented by the formula (1): ##STR3## wherein R.sup.1 is C.sub.1-20 alkyl, C.sub.6-12 aryl, C.sub.7-20 aralkyl or a group of the formula: EQU R.sup.4 --(A).sub.n -- PA1 (ii) 1 to 40 mol % of a polymer diol; PA1 (iii) 1 to 90 mol % of a chain extender; and PA1 (iv) 30 mol % or less of other active hydrogen-containing compound; the combined amount of the compounds (i) to PA1 (iv) being 100 mol %; and PA1 (i) A diol containing phosphorylcholine structure represented by the formula (1): ##STR11## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above, (ii) a polymer diol, PA1 (iii) a chain extender, and,
In the method (1), heparin or urokinase introduced to the material surface exhibits antithrombogenicity or lytic activity on thrombus at the early stage of introduction of the material. In a long-term use, however, the antithrombogenic agents tend to dissolve out, lowering the ability of the material. In other words, according to the methods (A), (B) and (C), a long-term use under physiological conditions generally results in easy release of heparin or the like, making it difficult to achieve sufficient performance of medical materials which are used as implanted in the living body for a long period. The method (D) is beneficial in that the covalently bonded heparin is unlikely to be released, but conventional bonding techniques often alter the conformation of D-glucose or D-gluconic acid constituting heparin, whereby the anticoagulant effect reduces.
The methods (C) and (D) require selection of materials containing a functional group usable for immobilization of heparin, or introduction of such a functional group into the material. Accordingly, these methods narrow the range of usable materials or deteriorate the mechanical strength of the material due to the introduction of the functional group. Moreover, the complicated manipulation may increase the steps necessary for preparing the material.
In the methods (2) and (3), antithrombogenicity can be imparted to the material by introducing a biocompatible functional group. As described above, when an anticoagulating mucopolysaccharide (e.g., heparin) or a fibrinolytic activator (e.g., urokinase) is immobilized on the material, the antithrombogenicity of the material reduces as the antithrombogenic agents dissolve out. It is therefore difficult to retain the antithrombogenicity for a long period. In contrast, a material into which a biocompatible functional group has been introduced can retain the antithrombogenicity during long-term contact with the living body.
Biocompatible functional groups recently actively researched include phosphorylcholine structures. Phosphorylcholine structures are analogous to the structure of a phospholipid forming biomembranes, i.e., phosphatidylcholine. Accordingly, high-molecular materials containing phosphorylcholine structures in the molecule have high affinity to the living body and are useful as antithrombogenic materials.
For example, polymers containing 2-methacryloyloxyethylphosphorylcholine is analogous in structure to phosphatidylcholine, one of the constituents of external walls of cells. When a phospholipid derived from the living body is made to be adsorbed on the polymer, the polymer forms a surface analogous to biomembranes and shows excellent blood compatibility (Japanese Unexamined Patent Publications Nos. 63025/1979 and 96200/1988). It is also reported that high blood compatibility can be achieved by introducing a phosphorylcholine group into the main chain of a polyurethane (Japanese Unexamined Patent Publications Nos. 500726/87, 134085/96 and No. 259654/96 and WO 86/02933). However, the disclosed materials do not have antithrombogenicity sufficient for use as medical materials.